Craniofacial defects are among the most common human malformations. We have developed a mouse model of facial clefting and defective cranial bone suture closure by generating a knockout of the Ski gene. The craniofacial abnormalities in Ski-null mice correctly predicted the involvement of human Ski in 1p36 deletion syndrome, a human disorder that includes open fontanelles and a low incidence of facial clefting among its diverse features. The incidence of clefting in Ski -null mice is strain-specific, and in mixed backgrounds is determined by a small number of modifier genes. We will use the strain dependent model of facial clefting to identify polymorphisms in modifier loci by their association with clefting in the C57BL/6J strain, but not in 129 mice that do not exhibit facial clefting. Modifiers of this type are likely to be involved in clefting in 1p36 patients, and may be involved in common forms of clefting which are influenced by multiple genes. Mechanistic studies will focus on Ski as a co-regulator of transcription related to the BMP pathway because the BMP-regulated genes, Msx-1, Msx-2 and Cbfa1 play critical roles in craniofacial development, and have been implicated in many facial and cranial disorders similar to those resulting from the loss of Ski. We will also search for genes in the affected craniofacial regions that are deregulated in the absence of Ski using microarray technology. Genes identified in this way are likely to play a role in these defects in mice and will make excellent candidates for genes likely to be involved in human craniofacial abnormalities. We propose to identify polymorphisms in the non-deleted allele of human Ski because loss of function mutations of that allele may underlie susceptibility to facial clefting and other defects in 1p36 patients. Finally, we will generate Ski transgenic mice to determine whether they reproduce the craniosynostosis phenotype resulting from a duplication of the Ski locus in humans. These studies will contribute to our understanding of the gene regulatory networks that control craniofacial development, and of how disruption of these networks result in craniofacial defects. ? ?
